“We thought we already knew pretty much everything there was to know about how M protein helps strep gain a foothold in the human body and avoid the immune system, so this was a totally unexpected discovery, and an especially dramatic thing for an immune cell to do,” says Dr. Victor Nizet, professor of pediatrics and pharmacy, who led a recent landmark study with Partho Ghosh, professor of chemistry and biochemistry at UCSD.

“The surprising discovery that strep’s M protein, alone, wipes out macrophages, but not other types of immune cells, and that macrophages’ self-sacrifice serves as an early warning of infection to the rest of the immune system, is kind of like a good news and bad news scenario,” Nizet says.

UCSD’s discovery, published August 7 in Nature Microbiology, reveals new roles for the well-studied M protein and for macrophages. Researchers say this new information should inform current strep vaccine strategies, many of which are based on M protein, and lead to new treatment approaches for invasive infections where hyper-immune responses can be detrimental.

The original discovery of the M protein’s powers was made by Andrés Valderrama, a postdoctoral fellow jointly supervised by Nizet and Ghosh, and the lead author of the mechanism described in the paper.

After noticing that macrophages in a laboratory dish quickly died after M protein exposure, Valderrama and fellow researchers wanted to determine why, and why it happens only to macrophages. They found that macrophages recognize strep bacteria and respond by activating genes that encode IL-1beta, a pro-inflammatory signaling molecule, and components of NLRP3, cellular machinery that manages inflammation.

At the same time, these macrophages also gobble up M proteins freed from the bacterial cell surface, triggering a second signal required for NLRP3 activation. As a result, macrophages quickly release IL-1beta as a warning signal to other parts of the immune system, but at a cost to themselves, according to research. They commit cellular suicide in the process, further escalating the inflammatory response. Inflammation is good when fighting an infection, but too much can lead to a number of health problems.

M protein, an abundant, tentacle-like molecule that projects from the bacterium’s surface, is strep’s most important virulence factor, the study states. M protein is known to help the bacteria adhere to human tissues, make it harder for immune cells to engulf the bacteria, and bind or inhibit other components of the human immune system such as antibodies and antimicrobial peptides.

While macrophages in a laboratory dish infected with live normal strep bacteria spew IL-1beta and then commit suicide, strep bacteria engineered to lack M protein do not have the same effect. For instance, mice administered with purified M protein, alone, produced significantly more IL-1beta than mice that received a control, according to the research. The more M protein they received, the more IL-1beta they generated.

These findings underscore the significant role strep and M protein have played in human history—important enough that the human immune system has evolved a rapid response system just for them, according to Nizet.

“Common group A Streptococcus (GAS) infections such as strep throat are treated effectively with antibiotics including penicillin,” Nizet tells DDNews. “However, the rapid progression of severe, invasive GAS infections such as necrotizing fasciitis, sepsis and toxic shock syndrome requires additional supportive care to preserve life and organ function.”

This research “identifies another potential benefit of therapeutic antibodies against M protein and/or the inclusion of carefully chosen M protein fragments in a group A streptococcal (GAS) vaccine—namely, the reduction of dangerous hyperinflammation during severe invasive GAS infections described above,” he says.
The journal paper and “earlier research from our group (LaRock et al.Science Immunology 2016) indicate that macrophage IL-1 is very critical in the natural innate immune response to GAS infection, and that we should endeavor to support this biological process to optimize host defense against the pathogen,” Nizet adds.

“Our own research is focused on how the host recognizes and takes up M protein to activate IL-1 signaling,” Nizet says. “We think we will find other similar processes operating with other infections, and understand better how the host distinguishes dangerous pathogens from harmless commensal bacteria to mount a rapid protective response.

“Many labs—including our own—are exploring the best approach to a safe and effective GAS vaccine.”

Valderrama adds, “Our study suggests that targeting M proteins with vaccines or antibodies or blocking the way macrophages bring it into the cell might prove clinically useful in cases where hyperinflammation has become a problem.

“But it’s a delicate balance. We don’t want to block the early warning signal altogether, or the immune system would lose its first line of defense against strep.”

The strep M protein “is under active consideration as a vaccine antigen,” Valderrama says. “The challenge is that human antibodies generated against M protein can cross-react with host tissue, leading to rheumatic fever, an autoimmune disease. UCSD and other researchers are looking for workarounds and ways to engineer out the immunogenic parts of the M protein.”

In the meantime, Nizet and Valderrama are also working to better understand how M proteins and macrophages interact. They have created a library of macrophage variants using CRISPR-Cas9, each with a different gene mutated, and will test each variant to find those that are resistant to M protein-induced suicide.